When an infectious agent gains access to the respiratory tract, the immune system must recognize the infectious agent, activate immune cells, recruit the immune cells to the lung and finally neutralize the infectious agent. It must do all of this quickly before the infectious agent proliferates to the point that it causes irreversible damage. The overall goal of this Program Project Grant (PPG) is to better understand how primary and recall immune responses to influenza infection are targeted to specific areas of the respiratory tract. We hypothesize that the mechanisms of T cell primary and recall responses to influenza are adapted to, or are dictated by, the unique structure of the respiratory tract. To address this responses to influenza are adapted to, or are dictated by, the unique structure of the respiratory tract. To address this hypotheses, the 4 Projects and 3 Cores of this PPG together have the following goals: 1, To investigate the relationship between respiratory tract immune responses (T cell subtypes), structure and function. 2, To define the immune response to influenza in the respiratory tract immune response (T cell subtypes), structure, and function. 2, To define the immune response to influenza in the respiratory tract in terms of influenza-specific T cell subsets. 3, To determine the roles of T1 and T2 CD4 influenza in the respiratory tract in terms of influenza-specific T cell subsets. 3, To determine the roles of T1 and T2 CD4 and CD8 T cell subtypes in primary and recall responses to influenza in the respiratory tract. 4, To determine how recall or memory responses to influenza infection of the respiratory tract are expressed. 5, To determine the factors regulating recruitment of lymphoid and non-lymphoid cells to inflammatory sites in the respiratory tract. The program brings together basic cutting-edge immunology (Drs. Dutton, Swain, and Lund) with respiratory virus immunology (Dr. Woodland) and lung infectious disease immunopathology (Dr. Harmsen) all served by a bioimaging core (Dr. Randall) and animal core (Dr. Lund) Together these investigators will address critical basic questions pertaining to lung immunology that the investigators can not address individually. We expect that results of experiments proposed in this PPG application will lead to a better understanding of the cellular and molecular mechanisms that mediate these responses. Such an understanding is critical to the rational development of immunotherapies that would augment these advantageous responses, yet limit the detrimental responses.